Oxidative stress and inflammation play a major role in the etiology of sperm dysfunction via induction of peroxidative damage to the plasma membrane. Furthermore, oxidative stress affects the integrity of the sperm nuclear and mitochondrial genomes, leading to DNA strand breaks, aberrant recombination and/or defective packing, as well as chromatin cross-linking (Agarwal 2005, 2008, 2011; Aitken 2010, 2011; Baumber 2003, Cavallini 2006, Makker 2009, Noblanc 2011, Simon 2011, Twigg 1998, Zini 2009).

 

The observation of correlations between reactive oxygen species (ROS) generation by washed human sperm suspensions and their fertilizing capacity is consistent with the clinical significance of oxidative damage to human spermatozoa; this significance is bolstered by the demonstration of loss of functional competence and high rates of DNA damage of human spermatozoa directly or indirectly exposed to hydrogen peroxide (Twigg 1998). When the source of ROS is intracellular, many of the classical antioxidants that are effective against extracellular oxidative stress prove useless. However, albumin sustains sperm motility in such instances (Twigg 1998). 

 

The H2S-cysteine-GSH connection (Gojon 2020) suggests that H2S may be used by cells to synthesize L-cysteine, which can then serve as a building block in protein synthesis. Sulfur-deficient diets, however, are common and may lead to cysteine deficiency-especially in males - and, consequently, to deficits in the biosynthesis of important cysteine-rich proteins such as so-called “cysteine-rich secretory proteins” (CRISPs). The CRISPs are found only in vertebrates, within the male reproductive tract.

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CRISPs have been implicated in many aspects of spermatogenesis, as well as in the actual process of fertilization (Koppers 2011), and downregulation of CRISP-2 mRNA by a factor of 4.3 in asthenospermic patients has been reported (Jing 2011). 

 

The high susceptibility toward irreversible oxidative damage of mammalian sperm cells may be attributed to:

• The particularly high content of polyunsaturated fatty acids (PUFAs), plasmalogens and sphingomyelins of their membranes (Agarwal 2008. 2011; Cavallini 2008, Cocuzza 2007, Kefer 2009, Makker 2009, Zini 2009); 

• The lack of adequate repair mechanisms for oxidative damage, derived from a dearth of cytosolic antioxidant enzymes associated with the loss of most of their cytoplasm upon spermiation (Baumber 2003, Chabory 2010, Cocuzza 2007, Makker 2009, Noblanc 2011); 

• Sperm cells are particularly rich in highly active mitochondria, because they need a constant supply of energy to support their motility; in fact, spermatozoa were the first cells found to generate significant levels of ROS (Noblanc 2011). These characteristics increase the probability of mitochondrial membrane damage by leaked ROS;

• Native CRISPs present unusually high numbers of thiolic (unoxidized) cysteine residues, which renders them especially sensitive to inactivation by oxidants. 

 

The results of a Phase II clinical trial involving an H2S prodrug developed by Sulfagenix (SG1002) were highly encouraging, especially when considered against a backdrop of marginally effective therapeutic options for male subfertility, which will be briefly discussed next.

 

In the three Cochrane reviews on “Antioxidants for male subfertility” (Showell 2011, 2014; Smits 2019), the authors assessed the effects of oral antioxidants on men with documented sperm DNA damage and/or with impaired semen parameters on the basis of clinical trials wherein the participants were randomly assigned to antioxidant versus placebo, an alternative antioxidant, or no treatment; they found that, overall, the current evidence is inconclusive.

 

This means that there is only limited scientifically acceptable evidence that antioxidant supplementation improves outcomes for subfertile couples or, in Ashok Agarwal’s words, that “the available forms of treatment have mostly produced only marginally satisfactory responses, even in the best of proper trials” (Agarwal 2011) and that many drugs are being used without any rationale. On the other hand, the recently published results of Wang et al. (Wang 2018) validate H2S supplementation as a scientifically sound approach to treatment of oxidative stress-related male subfertility. 

 

One additional consideration is warranted: semen quality is a marker not only of fecundity but also of general health; impaired semen quality has been associated with shorter life expectancy and enhanced long-term morbidity (Eisenberg 2014, 2015; Jensen 2009, Latif 2017). Therefore, SG1002 positive influence on semen quality is consistent with the effects of H2S on general health and lifespan. 

 

Preeclampsia, a pregnancy disorder characterized by elevated blood pressure and proteinuria, is a major obstetric problem that contributes to both maternal and fetal mortality and morbidity: it complicates about 3.5% of all pregnancies worldwide (Holwerda 2015). Several studies point to placenta as the key organ in preeclampsia. In 2013, Ahmed found that plasma levels of H2S were significantly decreased in preeclamptic women and that a slow-releasing H2S donor (GYY4137) restored fetal growth in a mouse model of preeclampsia (Ahmed 2013). Two years later, Possomato-Vieira et al. treated preeclamptic female rats with a fast-releasing H2S donor (NaHS) and reported that this resulted in attenuated systolic blood pressure and enhanced placental weight (Possomato-Vieira 2015).

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